5,278 research outputs found
A review of hot-melt extrusion: process technology to pharmaceutical products [Review article]
Over the last three decades industrial adaptability has allowed hot-melt extrusion (HME) to gain wide acceptance and has already established its place in the broad spectrum of manufacturing operations and pharmaceutical research developments. HME has already been demonstrated as a robust, novel technique to make solid dispersions in order to provide time controlled, modified, extended, and targeted drug delivery resulting in improved bioavailability as well as taste masking of bitter active pharmaceutical ingredients (APIs). This paper reviews the innumerable benefits of HME, based on a holistic perspective of the equipment, processing technologies to the materials, novel formulation design and developments, and its varied applications in oral drug delivery systems
The role of body mass index and diabetes in the development of acute organ failure and subsequent mortality in an observational cohort
INTRODUCTION: Several studies have shown a correlation between body mass index (BMI) and both the development of critical illness and adverse outcomes in critically ill patients. The goal of our study was to examine this relationship prospectively with particular attention to the influence of concomitant diabetes mellitus (DM). METHODS: We analyzed data from 15,408 participants in the Atherosclerosis Risk in Communities (ARIC) study for this analysis. BMI and the presence of DM were defined at baseline. We defined 'acute organ failure' as those subjects who met a standard definition with diagnostic codes abstracted from hospitalization records. Outcomes assessed included the following: risk of the development of acute organ failure within three years of the baseline examination; in-hospital death while ill with acute organ failure; and death at three years among all subjects and among those with acute organ failure. RESULTS: At baseline, participants with a BMI of at least 30 were more likely than those in lower BMI categories to have DM (22.4% versus 7.9%, p < 0.01). Overall, BMI was not a significant predictor of developing acute organ failure. The risk for developing acute organ failure was increased among subjects with DM in comparison with those without DM (2.4% versus 0.7%, p < 0.01). Among subjects with organ failure, both in-hospital mortality (46.5% versus 12.2%, p < 0.01) and 3-year mortality (51.2% versus 21.1%, p < 0.01) was higher in subjects with DM. CONCLUSION: Our findings suggest that obesity by itself is not a significant predictor of either acute organ failure or death during or after acute organ failure in this cohort. However, the presence of DM, which is related to obesity, is a strong predictor of both acute organ failure and death after acute organ failure
The validity and responsiveness of three quality of life measures in the assessment of psoriasis patients: results of a phase II study
BACKGROUND: Patient-reported outcome (PROs) measures are being used more frequently in investigational studies of treatments for moderate to severe plaque psoriasis. The objective of this study was to examine the relationships among the Dermatology Life Quality Index (DLQI), the Short Form 36 (SF-36), and the EuroQOL 5D (EQ-5D) and to assess their validity, responsiveness, and estimates of minimum important differences. METHODS: A Phase II, randomized, double-blind, parallel group, placebo-controlled, multi-center clinical trial assessed the clinical efficacy and safety of two doses of subcutaneously administered adalimumab vs. placebo for 12 weeks in the treatment of 147 patients with moderate to severe plaque psoriasis. This study provided the opportunity to evaluate the validity and responsiveness to change in clinical status of PROs instruments. Patients completed the DLQI, SF-36, and EQ-5D questionnaires at baseline and at 12 weeks. Blinded investigators assessed the Psoriasis Area and Severity Index (PASI) scores and the Physician's Global Assessment (PGA) scores of enrolled patients. The responsiveness of the measures to changes in the clinical endpoints from baseline to Week 12 was assessed. Estimates of minimum important differences (MID) were derived. All analyses were performed with blinded data; findings and conclusions were not biased based on treatment condition. RESULTS: The dermatology-specific DLQI was highly correlated to clinical endpoints at baseline and at Week 12, and was the most responsive PRO to changes in endpoints. Compared with the SF-36, the EQ-5D index score and VAS scores were generally more highly correlated with clinical endpoints, but displayed about the same degree of responsiveness. The most responsive SF-36 scales were the Bodily Pain and Social Functioning scales. Estimates of the MID for the DLQI ranged from 2.3–5.7 and for the SF-36 Physical Component Summary (PCS) score ranged from 2.5–3.9. CONCLUSION: This study provides support for the continued use of the DLQI and SF-36 PCS in the assessment of treatments for psoriasis. On the basis of the results from this trial, the EQ-5D should be considered as a general PRO measure in future clinical trials of patients with moderate to severe plaque psoriasis
Catalytic Activity and Fluxional Behavior of Complexes Based on RuHCl(CO)(PPh<sub>3</sub>)<sub>3</sub> and Xantphos-Type Ligands
With RuHCl(CO)(PPh3)3 as the starting material, the complexes RuHCl(CO)(PPh3)(L) were prepared for L = Xantphos and closely related ligands. Their catalytic activity in the direct amination of cyclohexanol showed large differences depending on the different backbone structures. In those complexes the Xantphos-type ligand backbones are slightly bent and display fluxionality, studied by VT-NMR. This was assigned to the "flipping" of the backbone via the bridging atoms in the xanthene backbone. Via line shape analysis of the peaks, the Gibbs free energy of activation of the flipping movement was found to be around 56 kJ/mol in all cases. However, the activation enthalpy and entropy differed considerably. Employing RuCl2(PPh3)3 as the precursor resulted in the trans-coordinated complexes RuCl2(PPh3)(L) for L = Xantphos, Sixantphos. Fluxionality was no longer observed, due to the fact that in these complexes the O atom in the backbone also coordinates to the Ru
The Role of Dopamine in Drosophila Larval Classical Olfactory Conditioning
Learning and memory is not an attribute of higher animals. Even Drosophila larvae are able to form and recall an association of a given odor with an aversive or appetitive gustatory reinforcer. As the Drosophila larva has turned into a particularly simple model for studying odor processing, a detailed neuronal and functional map of the olfactory pathway is available up to the third order neurons in the mushroom bodies. At this point, a convergence of olfactory processing and gustatory reinforcement is suggested to underlie associative memory formation. The dopaminergic system was shown to be involved in mammalian and insect olfactory conditioning. To analyze the anatomy and function of the larval dopaminergic system, we first characterize dopaminergic neurons immunohistochemically up to the single cell level and subsequent test for the effects of distortions in the dopamine system upon aversive (odor-salt) as well as appetitive (odor-sugar) associative learning. Single cell analysis suggests that dopaminergic neurons do not directly connect gustatory input in the larval suboesophageal ganglion to olfactory information in the mushroom bodies. However, a number of dopaminergic neurons innervate different regions of the brain, including protocerebra, mushroom bodies and suboesophageal ganglion. We found that dopamine receptors are highly enriched in the mushroom bodies and that aversive and appetitive olfactory learning is strongly impaired in dopamine receptor mutants. Genetically interfering with dopaminergic signaling supports this finding, although our data do not exclude on naïve odor and sugar preferences of the larvae. Our data suggest that dopaminergic neurons provide input to different brain regions including protocerebra, suboesophageal ganglion and mushroom bodies by more than one route. We therefore propose that different types of dopaminergic neurons might be involved in different types of signaling necessary for aversive and appetitive olfactory memory formation respectively, or for the retrieval of these memory traces. Future studies of the dopaminergic system need to take into account such cellular dissociations in function in order to be meaningful
Smaller & Sooner: Exploiting High Magnetic Fields from New Superconductors for a More Attractive Fusion Energy Development Path
The current fusion energy development path, based on large volume moderate magnetic B field devices is proving to be slow and expensive. A modest development effort in exploiting new superconductor magnet technology development, and accompanying plasma physics research at high-B, could open up a viable and attractive path for fusion energy development. This path would feature smaller volume, fusion capable devices that could be built more quickly than low-to-moderate field designs based on conventional superconductors. Fusion’s worldwide development could be accelerated by using several small, flexible devices rather than relying solely on a single, very large device. These would be used to obtain the acknowledged science and technology knowledge necessary for fusion energy beyond achievement of high gain. Such a scenario would also permit the testing of multiple confinement configurations while distributing technical and scientific risk among smaller devices. Higher field and small size also allows operation away from well-known operational limits for plasma pressure, density and current. The advantages of this path have been long recognized—earlier US plans for burning plasma experiments (compact ignition tokamak, burning plasma experiment, fusion ignition research experiment) featured compact high-field designs, but these were necessarily pulsed due to the use of copper coils. Underpinning this new approach is the recent industrial maturity of high-temperature, high-field superconductor tapes that would offer a truly “game changing” opportunity for magnetic fusion when developed into large-scale coils. The superconductor tape form and higher operating temperatures also open up the possibility of demountable superconducting magnets in a fusion system, providing a modularity that vastly improves simplicity in the construction, maintenance, and upgrade of the coils and the internal nuclear engineering components required for fusion’s development. Our conclusion is that while tradeoffs exist in design choices, for example coil, cost and stress limits versus size, the potential physics and technology advantages of high-field superconductors are attractive and they should be vigorously pursued for magnetic fusion’s development
The effect of different combinations of vascular, dependency and cognitive endpoints on the sample size required to detect a treatment effect in trials of treatments to improve outcome after lacunar and non-lacunar ischaemic stroke
Background
Endpoints that are commonly used in trials of moderate/severe stroke may be less frequent in patients with minor, non-disabling stroke thus inflating sample sizes. We tested whether trial efficiency might be improved with composite endpoints.
Methods
We prospectively recruited patients with lacunar and minor non-lacunar ischaemic stroke (NIHSS ≤ 7) and assessed recurrent vascular events (stroke, transient ischaemic attack (TIA), ischemic heart disease (IHD)), modified Rankin Score (mRS) and cognitive testing with the Addenbrooke’s Cognitive Examination (ACE-R) one year post-stroke. For a potential secondary prevention randomised controlled trial (RCT), we estimated sample sizes using individual or combined outcomes, at power 80% (and 90%), alpha 5%, required to detect a relative 10% risk reduction.
Results
Amongst 264 patients (118 lacunar, 146 non-lacunar), at one year, 30/264 (11%) patients had a recurrent vascular event, 5 (2%) had died, 3 (1%) had clinically-diagnosed dementia, 53/264 (20%) had mRS ≥ 3 and 29/158 (19%) had ACE-R ≤ 82 (57 could not attend for cognitive testing). For a potential trial, at 80% power, using mRS ≥ 3 alone would require n > 5000 participants, recurrent vascular events alone n = 9908 participants, and a composite of any recurrent vascular event, ACE-R ≤ 82, dementia or mRS ≥ 2 (present in 56% of patients) n = 2224 patients. However, including cognition increased missing data. Results were similar for lacunar and non-lacunar minor ischaemic stroke.
Conclusions
Composite outcomes including vascular events, dependency, and cognition reduce sample size and increase efficiency, feasibility, and relevance to patients of RCTs in minor ischaemic stroke. Efficiency might be improved further with more practical cognitive test strategies
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